Mantle cell lymphoma (MCL), characterized by a t(11;14) translocation that results in up-regulation of cyclin D1, is incurable with standard chemotherapy. Several new drugs are currently undergoing early clinical testing in MCL. Recent phase II studies have shown that bortezomib (BZM), an inhibitor of the proteasome, can induce responses in about 50% of pre-treated patients. Bortezomib is more active against Mantle Cell Lymphoma than against most other lymphoma subtypes. Nevertheless, up to half of patients with MCL have bortezomib resistant disease. Factors contributing to intrinsic resistance to bortezomib have not been determined. We used a panel of 8 bortezomib sensitive and 3 relatively bortezomib resistant cell lines to investigate differences in tumor biology that could determine sensitivity to bortezomib. Bortezomib effectively inhibited high baseline proteasome activity and induced a comparable degree of proteasome inhibition in both sensitive and resistant cells. At 10nM bortezomib induced the pro-apoptotic BH3 only protein NOXA in sensitive but not resistant cells. However, at higher concentrations NOXA was upregulated in relative resistant cells and was sufficient to induce apoptosis arguing against a defect in NOXA regulation or function as the basis of bortezomib resistance. Bortezomib was equally effective against cells with high and low constitutive NF-B signaling. Also, sensitive and resistant MCL cell lines showed comparable activation of the AKT pathway. We conclude that bortezomib can overcome classic mechanisms of resistance to apoptosis and that determinants of bortezomib sensitivity in MCL are due to differences in signaling or stress pathways upstream of Noxa. To investigate the molecular effects of BZM on tumor biology in vivo we analyzed gene expression changes in patients with the leukemic form of MCL during treatment with BZM. Distinct functional gene expression signatures induced by BZM contained numerous genes encoding proteasome components, heat shock proteins, chaperones, detoxifying enzymes and pro-apoptotic factors. The dominant gene expression signatures were those driven by transcription factors that can mediate the endoplasmic reticulum (ER) stress response also known as the unfolded protein response. Under physiologic conditions, the ER stress response can help restore homeostasis and protect from apoptosis, while an overwhelming insult can lead to activation of pro-apoptotic mechanism. To define these effects in more detail, we used MCL cell lines characterized for their sensitivity to BZM. In these cell lines BZM induced the same gene expression signatures as observed in patient samples. Strong up-regulation of the ER-stress response was evident in BZM sensitive cells and correlated with induction of the pro-apoptotic BH3 only protein Noxa. Inhibition of Noxa up-regulation by RNAi protected cells from BZM induced apoptosis indicating that Noxa is a major effector mechanism of BZM induced cell death. Ongoing studies aim to identify the molecular basis for the observed variability in the activation of pro-apoptotic mechanisms by BZM.